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In primary aldosteronism (PA), autonomous overproduction of the salt-retaining mineralocorticoid hormone, aldosterone, by the adrenal cortex leads to the suppression of its normal principal regulator, renin/angiotensin II.1 Aldosterone overproduction results in salt and water retention, causing hypertension and urinary K+ wasting, which eventually may lead to hypokalemia.1 Although once thought to account for <1% of hypertension, evidence accumulated during the past 2 to 3 decades suggests that the prevalence is much higher (5% to 10%) and most patients are normokalemic.2–4

Early diagnosis of PA is important because optimal hypertension control is often achieved only with either aldosterone receptor antagonists (spironolactone and eplerenone) or epithelial Na+ channel blockers (amiloride). Adrenal venous sampling selects those with aldosterone-producing adenoma from those with bilateral adrenal hyperplasia5 with the possibility of surgical cure. Furthermore, aldosterone excess has adverse effects in addition to those of hypertension alone–cardiac and vascular remodeling and fibrosis, heart attack, arrhythmias, stroke, and renal damage,6 making it imperative not to miss PA.

The US Endocrine Society guideline on detection, diagnosis, and management of PA has recommended that, instead of proceeding directly to subtype classification, patients who screen positive for PA by demonstrating elevated plasma aldosterone/renin ratio levels should undergo further testing to definitively confirm or exclude the diagnosis.7 This approach recognizes the possibility that elevated aldosterone/renin ratio values may represent false positives and permits identification of individuals who, by testing negative (PA excluded), can be spared from having to undergo adrenal venous sampling, which is expensive, technically difficult and invasive. The guideline, however, has so far regarded available evidence as insufficient to recommend any one of the 4 testing procedures in common use (oral sodium loading, saline infusion suppression testing [SIT], fludrocortisone suppression testing [FST], and captopril challenge) over the others.

Although FST has been regarded by some as the most reliable confirmatory test,8 few centers have adopted its use on a routine basis primarily because of the complexity and expense of the protocol involved. For example, we have found it necessary to admit patients to hospital for the 5 days duration of FST to enable and guarantee control of posture, diet, blood pressure, and plasma potassium levels.8 Potassium is held within the normal range by appropriate doses of slow-release KCl supplementation adjusted daily based on the plasma levels measured 3 to 4 times per day. SIT has been in use since the 1970s and is still favored by many because it is much easier to perform than FST and can be conducted on an outpatient basis.

The current issue of Hypertension contains an important article by Cornu et al,9 which reports a high false-negative rate (12 [12%] of 102 patients missed using a cut-off plasma aldosterone level of 139 pmol/L [5 ng/dL]) for unilateral PA associated with SIT. By focusing on unilateral PA, they left the question as to whether these patients truly had PA in little doubt. This is in contrast to many other studies that have attempted to assess the validity of confirmatory tests (such as SIT) by comparing one test to another and not to a “gold standard”. Although the demonstration of lateralization of aldosterone production on adrenal venous sampling is not a perfect gold standard for PA (partly because of the diversity of approaches and diagnostic criteria for lateralization), it is nevertheless reasonably convincing, especially given the careful clinical approach taken by the investigators and the reasonably stringent lateralization criteria that they applied. Furthermore, as unilateral (as opposed to bilateral) PA is potentially curable by unilateral adrenalectomy, it is especially important not to miss this subtype, and hence particularly concerning that so many patients with potentially curable PA would have been excluded from further workup (including adrenal venous sampling) if the investigators had relied solely on SIT for definitive confirmation or exclusion of the diagnosis of PA (as indeed many other groups do). Instead, they diagnosed patients as having PA on the basis of 2 high aldosterone/renin ratios and a high plasma aldosterone, even if the SIT was negative, and this provided them with the opportunity to observe and assess rates of false negativity associated with the SIT.

Importantly, SIT was performed in the recumbent position, and this is highly likely to have contributed to its lack of sensitivity. For patients with angiotensin-responsive forms of PA (unilateral or bilateral), recumbent aldosterone levels are lower than upright, and tend to be lower than in those with angiotensin-unresponsive forms, and hence do not have as far to fall to reach the cutoff for normal suppression.10 In a recently conducted pilot study, we reported recumbent SIT to be positive in only 8 of the 24 patients with PA, using FST as the gold standard.11 Almost all of those missed were angiotensin-responsive (defined as a rise in aldosterone of at least 50% above basal in response to upright posture). Recumbent SIT missed the only patient in the study with unilateral, angiotensin-responsive PA. By contrast, when these patients underwent SIT in the seated position, seated SIT was positive in 23 of the 24 patients (including the patient with unilateral, angiotensin-responsive PA). It is, therefore, important that the findings of Cornu et al9 are not generalized to all forms of suppression testing (including seated SIT or FST, both of which use upright aldosterone levels rather than supine), but instead are limited to recumbent SIT. Because recumbent SIT is probably the most common approach used in centers around the world, the significance of their findings remains high.

As acknowledged by the authors, limitations of the study included its retrospective design. Another weakness was the use of recumbent (rather than upright) samples to screen for PA that may have led to a selection bias for patients with angiotensin-unresponsive forms of PA (who, as stated above, tend to have higher recumbent aldosterone levels than those with angiotensin-responsive forms).11 However, if anything, this may have led to an improvement (rather than a decline) in the performance of the recumbent SIT as we have found it to be much better at detecting angiotensin-unresponsive versus responsive forms of PA.11 Because the patients in the study by Cornu et al seem not to have undergone the measurement of both recumbent and upright plasma aldosterone, the authors were unable to examine the relationship between the results of posture testing and those of SIT.

Although seated SIT holds promise as being a more reliable alternative to the traditional recumbent SIT, it requires validation with larger patient numbers, and an ongoing study (aiming for around 130 patients, comprising approximately 100 with and 30 without PA) is being conducted within our center to address this issue with results expected to be available within the next 12 months or so. In the meantime, for institutions which rely on the recumbent SIT for confirmatory testing, it would seem appropriate to exercise caution before ruling out PA (unilateral or bilateral) on the basis of a negative study, especially if that patient is known to demonstrate responsiveness of plasma aldosterone to upright posture.

Sources of Funding

Original work described in this article was supported by the National Health and Medical Research Council of Australia.

Disclosures

None.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.